PROJECT SUMMARY Childhood obesity predisposes adults for metabolic susceptibility to obesity and type 2 diabetes. Therefore, identifying early regulatory factors to prevent childhood obesity is critical for combating the current obesity epidemic. Brown adipose tissue (BAT) is a specialized fat that dissipates excess energy into heat counteracting obesity. Current research renews the metabolic function of BAT demonstrating that BAT is a crucial regulator in maintaining energy balance by increasing thermogenic energy expenditure. Given that BAT is formed prenatally and its retainment alters propensity for weight gain in later life, enhancement of BAT development during pregnancy holds promise for prevention of childhood obesity. The long-term goal of this proposal is to develop therapeutic strategies to combat obesity by boosting BAT activity. The objective of this application is to evaluate the role of maternal supply of n-3 PUFA as a molecular driver to stimulate prenatal BAT formation and mitigate metabolic susceptibility to obesity in offspring. Based on preliminary results, the central hypothesis to test is that maternal supply of n-3 PUFA promotes the embryonic BAT development via histone acetylation and microRNA (miRNA)-mediated epigenetic mechanisms, which results in increased postnatal BAT retainment and decreased risk of obesity and T2D in later life. This project will pursue the two specific aims. Specific Aim1 will determine the mechanism by which maternal n-3 PUFA intake modulates the transcriptional reprogramming of fetal BAT. We will evaluate the impact of maternal n-3 PUFA nutrition on epigenetic modification including the genome-wide H3K27Ac pattern and pri-miRNA processing efficiency. Specific Aim2 will identify the metabolic significance of maternal n-3 PUFA supplementation in postnatal BAT retainment and long-term metabolic ramification. The proposed work will explore a novel signaling pathway that links maternal n-3 PUFA intake to prenatal BAT reprogramming. Results of this application will provide seminal evidence establishing the innovative role of prenatal exposure of n-3 PUFA on BAT formation at the time of birth, post-natal retention, and its long-term metabolic implications.